Myocardial recovery in children supported with a durable ventricular assist device—a systematic review

Abstract OBJECTIVES A small percentage of paediatric patients supported with a ventricular assist device (VAD) can have their device explanted following myocardial recovery. The goal of this systematic review is to summarize the current literature on the clinical course in these children after weaning. METHODS A systematic literature search was performed on 27 May 2022 using Embase, Medline ALL, Web of Science Core Collection, Cochrane Central Register of Controlled Trials and Google Scholar to include all literature on paediatric patients supported by a durable VAD during the last decade. Overlapping study cohorts and registry-based studies were filtered out. RESULTS Thirty-seven articles were included. Eighteen of them reported on the incidence of recovery in cohort studies, with an overall incidence rate of 8.7% (81/928). Twenty-two of the included articles reported on clinical outcomes after VAD explantation (83 patients). The aetiologies varied widely and were not limited to diseases with a natural transient course like myocarditis. Most of the patients in the included studies (70; 84.3%) were supported by a Berlin Heart EXCOR, and in 66.3% (55/83), only the left ventricle had to be supported. The longest follow-up period was 19.1 years, and multiple studies reported on long-term myocardial recovery. Fewer than half of the reported deaths had a cardiac cause. CONCLUSIONS Myocardial recovery during VAD support is dependent on various contributing components. The interactions among patient-, device-, time- and hospital-related factors are complex and not yet fully understood. Long-term recovery after VAD support is achievable, even after a long duration of VAD support, and even in patients with aetiologies different from myocarditis or post-cardiotomy heart failure. More research is needed on this favourable outcome after VAD support.


INTRODUCTION
Every year the number of paediatric patients receiving a ventricular assist device (VAD) for end-stage heart failure is increasing, with currently over one-third of the patients receiving transplants being bridged with one [1,2].According to registry data, most children are bridged to a transplant, but a small number of children (7.5-11.3%)can have the VAD explanted because they undergo myocardial recovery [1,3].This outcome is particularly interesting because it could potentially postpone or even prevent a heart transplant and the accompanying life-long immunosuppression, morbidity and risk of death.The scarcity of donor hearts, especially among the youngest children, and the increasing waiting list times make this an even more favourable outcome [4,5].
Although explantation of durable VADs has been reported, less is known about post-explantation outcomes.It is uncertain whether this gain in myocardial function is sustainable or if these hearts cannot last without mechanical support and deterioration at a certain point is inevitable.In adults, survival without recurrence of heart failure of 88% after 2 years has been reported [6].In children, few small cohort studies report outcomes after recovery [7,8], and most of what is known is based on case reports and case series [9][10][11].This situation hampers evidence-based decision making regarding the weaning of the device in daily practice.
The goal of this systematic review was to search the recent literature on the explantation rate of durable VADs due to myocardial recovery in children and investigate the clinical course after explantation.

METHODS
A systematic literature search using Embase, Medline ALL, Web of Science Core Collection, Cochrane Central Register of Controlled Trials and Google Scholar was performed by staff of the medical library of the Erasmus Medical center on 27 May 2022.Google Scholar was added only to assure that no articles were missed.The complete list of search terms can be found in the supplementary material.This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
In this systematic review, we answered 2 questions: In the first section, we investigated the incidence of recovery in paediatric patients supported by durable VADs.To this end, all cohort studies with at least 20 children supported by a durable VAD were included and tabulated.
In the second section of this paper, the follow-up after explantation of a durable VAD due to myocardial recovery was examined.To do so, all papers reporting a clinical course after weaning were included and tabulated.
Further inclusion and exclusion criteria are depicted in Table 1.
Patients supported by a right ventricular assist device (RVAD) only were excluded from this review because the aetiology of right ventricle failure and recovery is essentially different from the aetiology and possible recovery of the left ventricle [12].However, to avoid excluding large cohort studies, which are important to answer our research questions, studies with less than 3% supported by an RVAD only were included.
Two researchers (SR and MS) reviewed the papers independently and created a list of papers that met the inclusion criteria.Any discrepancies between the 2 lists were resolved through discussion until a consensus was reached.
Multiple studies were found to have overlapping cohorts.In case of overlapping study cohorts, only the most recent cohort study was included.
From the included studies, the following data-if available in the full text-were extracted: For the outcomes after VAD support, percentages were calculated and presented.
Due the scarcity of VAD explants after myocardial recovery and the therefore often small studies, all data, including outlier data, are presented and summarized in the tables.No statistical analysis other than calculation of percentages was performed due to the heterogeneity and the small size of the patient population.

RESULTS
After the search, 4185 articles were identified.A total of 1581 articles were excluded because they were published before 2012.Another 2372 articles were excluded based on title or abstract.Of the remaining 232 articles, the full text was screened and an additional 195 manuscripts were excluded.Finally, 37 articles were included in this systematic review (Fig. 1).After the first screening, the reviewers disagreed on the inclusion of 110 articles (2.6%).These disagreements were resolved through discussion.
To investigate the incidence of recovery in cohort studies (first section, Table 2), non-registry-based studies with a minimum of 20 paediatric patients supported by a durable VAD were included (18 studies).To investigate follow-up after VAD explantation (second section, Table 3), all studies that reported the clinical course in paediatric patients after the explantation of a durable VAD were included (22 studies).Three studies were included for both research questions.

Follow-up after recovery
Twenty-two articles were included to investigate outcomes after the durable VADs were explanted.Most of these articles were case reports (12/22) or case series (6/22).Table 3 presents the 22 included studies sorted by type of device.In most of these studies, the durable VAD used was the BHE (13 of the 22 included studies), followed by the HeartWare (Medtronic, Framingham, MA, USA) (HVAD; 4 of the 22 included studies).
In the 22 identified articles, a total of 83 patients with durable devices were identified.Aetiology varied widely and was not limited to diseases with a natural transient course like myocarditis (Fig. 2).Structural heart diseases (other than in the case of postcardiotomy heart failure) and even a few cases of ischaemic cardiomyopathy were included.Most of the patients (70; 84.3%) were supported by a BHE followed by the paracorporeal Thoratec Ventricular Assist Device (PVAD; 6; 7.2%) (Thoratec, Pleasanton, CA, USA) and an HVAD (5; 6.0%).In 55 (66.3%) patients, a left ventricular assist device (LVAD) was implanted; in 15 (18.1%), a BiVAD; in 1 (1.2%) an RVAD; and in 5 (6.0%), a single ventricular assist device.One study (with 7 patients included) did not report on the type of support.
The duration of follow-up varied widely, and the maximum follow-up was 19.1 years.Twelve of the 83 patients (14.5%) died during the follow-up period.Causes of death varied and were not all related to heart failure.Cardiac causes of death included cardiogenic shock in 1 patient, cardiac failure in 1, ventricular arrhythmias in 1 and persistent cardiopulmonary failure (hypoxia and hypercarbia) with concomitant multiple organ failure in 1.Other causes of death included a massive haemorrhagic cerebrovascular accident in 1, septic shock in 1 and redirection of care due to mitochondrial disease plus failure to wean from ventilator support and poor long-term prognosis in 1.In 5 cases the cause of death was not reported (Tables 3, 4).
During the follow-up period, at least 3 patients needed VAD reimplants and 2 needed cardiac transplants.Caution should be taken since the different studies reported outcomes in various ways.For example, some studies only reported a survival rate, without describing cardiac function.

DISCUSSION
This systematic review summarizes the recent literature on the incidence of myocardial recovery in children supported with a durable VAD.Most studies reported an incidence between 0 and 15% with an overall incidence of 8.7%.This finding is in accordance with the reported incidence of recovery in large registries [1,3].
Figure 2: Range of aetiologies in patients with myocardial recovery after VAD support.Aetiologies are scaled based on the prevalence of diagnosis reported by the studies included in table 3. Of note, many studies reported overlapping/concomitant aetiologies, and this is not meant as a representation of the actual incidence of the different types of aetiology in this subpopulation.This figure has been designed using images from Flaticon.com.Tx: heart transplantation The researchers reported a wide range of recovery rates up to 38.1% [13].Incidence rates can be influenced by various factors.First, aetiology: A population with a higher percentage of more transient types of diseases, e.g.acute myocarditis or postcardiotomy failure, is more likely to have higher incidence rates of recovery compared to progressive or structural diseases.After bridging the acute phase with VAD support, the natural course of the disease allows improvement in cardiac function and weaning from the device.Myocarditis was associated with higher myocardial recovery [odds ratio (OR) 17.56, 95% confidence interval (CI) 4.6-67.4) in a study from Miera et al. that included almost 150 patients [7].However, our group performed a multivariable Cox regression analysis using the paediatric European Registry for Patients with Mechanical Circulatory Support (EUROMACS) on 303 BHE-supported children and found no significant association between primary diagnoses and recovery (non-CHD versus CHD: hazard ratio 0.919, 95% CI 0.525-1.611,P = 0.771) [26].This review also showed that myocarditis and post-cardiotomy failure are not the only diagnoses associated with successful VAD explantation due to recovery.
Second, the type of device seems to matter.It is thought that the key mechanism to myocardial recovery is left ventricular unloading, which pulsatile devices seem to achieve better than continuous devices [27].In a study that included close to 400 patients (paediatric and adult), patients with pulsatile-flow LVAD were almost 3 times more likely to have their device explanted due to a gain in myocardial function [28].The majority of patients included in this systematic review were supported by pulsatile devices.This fact might support the aforementioned study, although no strong conclusions can be drawn from it.
Third, the duration of VAD support is likely to affect recovery.A diseased heart needs sufficient time to recover but, on the other hand, it is plausible that in children in whom recovery does not occur in the first months, myocardial recovery is unlikely to happen suddenly thereafter.This observation is supported by the results of a molecular study by Madigan et al. [29] that show maximum structural reverse remodelling by about 40 days.However, multiple studies included in this systematic review report on cases of myocardial recovery after 6 months of support or more [30][31][32][33][34].Moreover, a potential late recovery might be missed if a donor heart becomes available early before recovery occurs.
Another factor that is sometimes suggested to influence recovery rates is the general condition of the patient.One could argue that sicker children (reflected for example in their INTERMACS classification or the need for ECMO prior to VAD support) have less favourable outcomes and therefore a lower chance of myocardial recovery.On the other hand, in the included study with the highest recovery rate (38.1%), 60% of the children were classified as INTERMACS I and one-third were supported by ECMO prior to VAD support [13].INTERMACS classification, previous ECMO or previous intubation was not significantly associated with multivariable analyses in BHE-supported children [26].
Furthermore, age and body surface area are associated with myocardial recovery.A previous report from our group showed significantly higher recovery rates in BHE-supported children with a body surface area < 0.53 m 2 compared to children with a higher body surface area (21.8% vs 4.3-7.6% at 1 year, P = 0.00534) [26].Similarly, Miera et al. [7] showed a more than fivefold increased recovery rate for children under 2 years of age (OR 5.64, 95% CI 2.0-16.6).Some of our included studies seem to reflect this too.For example, some studies with older patients show lower recovery rates [15,16,21,25], whereas others with younger children show higher recovery rates [22,35].
Lastly, the lack of universally accepted, evidence-based protocols for both implanting and possible weaning of VAD support are likely to shape outcome as well as recovery rates [36].In the last few years, a few protocols have been suggested in the literature [7,8,32,34,37,38].Although most of them use echocardiographic parameters and vital signs such as heart rate and blood pressure to evaluate myocardial recovery, substantial differences exist among them.For example, invasive haemodynamic measurements are often done, but various thresholds are used [7,34,37,38], and some centres are not convinced of the added value of Swan Ganz measurements to select patients for VAD explantation [8].Additionally, a minimum duration of support is sometimes included in the criteria before myocardial recovery is evaluated [8,34], and the duration of off-pump trials varies widely [7,32,34,38].Furthermore, not all patients who are weaned meet all weaning criteria [37].Suboptimal parameters can be accepted in a specific patient with high complication rates.This so-called "forced" weaning could potentially be less successful.Additionally, some institutional protocols use a temporary mechanical circulatory support system instead of a durable one if recovery can be expected.
One important question after durable VAD explantation remains long-term follow-up.As seen in this review, many studies do not report long-term data, but some papers show that long-term myocardial recovery after a VAD is explanted is achievable.Twelve of the 83 (14.5%) patients previously supported by a durable VAD died during follow-up.The actual proportion might be higher due to limited follow-up time in some papers and due to publication bias.Post-explantation causes of death were not always cardiac, although most of them probably are related to the hospitalization and a certain general weakness Besides the aforementioned reasons for possibly underestimated mortality rates, which also apply to the rates of ECMO/VAD and/ or HTx, the latter might also be higher due to the various ways of reporting on outcomes in the different case reports.For example, sometimes only a survival percentage is mentioned, without further specifying any possible recurrent heart failure.
In adults, explantation due to myocardial recovery only occurs in a small percentage of the patients [39,40].Independent predictors for this outcome were-inter alia-younger age (<50 year; OR 2.5), non-ischaemic aetiology (OR 5.4%), time since initial diagnosis (<2 years; OR 3.4) and type of device (axial vs centrifugal flow; OR 7.6) [41].Remarkably, only a small percentage of patients with substantial recovery undergo explantation [41,42].Suggested reasons for this discrepancy are uncertainty regarding post-explant outcomes, limited experience with explanting VADs and a heart transplant being the "gold standard" of treatment [43,44].

LIMITATIONS
This systematic review summarizes the available literature on the incidence and follow-up after weaning from a durable VAD due to myocardial recovery.Conclusions from this study have to be interpreted cautiously because of the high heterogeneity of this population.Children of all ages, with various aetiologies and INTERMACS classifications, supported for different durations by different types of VADs, were included.A meta-analysis was not possible due to the heterogeneity of the population; thus this paper merely serves as an overview of what is known.No analyses to determine risk factors for recovery could be done.
Another important limitation of this study is publication bias.It is possible that, especially for case reports on follow-up after recovery, successful clinical courses were more likely to be reported and published.Furthermore, this review depended on what was reported.Therefore, we were limited to providing a homogeneous and extensively detailed overview.For example, it cannot be ruled out that some of the devices registered as LVAD or RVAD were actually single ventricular assist devices.
Furthermore, although pharmacological therapy is of paramount importance in this specific population, drug therapy was rarely reported in the included studies.Therefore, it was not mentioned further in this manuscript.
Lastly, one must consider that the VAD experience summarized here is an experience from the last few decades.In these years, many potentially contributing factors have changed: Experience has increased, devices have evolved and protocols have been developed and altered.This situation hampers the interpretation of the results.

CONCLUSION
Myocardial recovery during VAD support is a scarce but the most favourable outcome, especially in light of high waiting list mortality, scarcity of donor hearts and the higher morbidity and mortality after a cardiac transplant.This outcome is, however, dependent on various contributing components.The interactions among patient-(age, aetiology, INTERMACS classification), device-(pulsatile/continuous, LVAD/BiVAD), time-(duration of support, duration of disease, duration of follow-up) and hospital-(experience, protocols used) related factors are complex and not yet fully understood.However, long-term survival after explanting a VAD seems achievable, even after long-term VAD support and even in patients with aetiologies different from myocarditis or post-cardiotomy heart failure.This valuable outcome should be better investigated in order to optimize this therapeutic strategy.To do so, joint efforts are needed, and we encourage large registries to include follow-up data after explantation.

Figure 1 :
Figure 1: Article selection: 232/4185 articles were identified for full-text screening; 195 of the 232 articles were excluded for various reasons; 37 articles were included in the study; Table2was compiled from 15 articles.Nineteen articles were used to compile Table3.Three articles were included in both tables.ECMO: extracorporeal membrane oxygenation, HTX: heart transplantation, TAH: total artificial heart, VAD: ventricular assist device.

Table 1 :
Inclusion and exclusion criteria

Table 2 :
Incidence of recovery

Table 3 :
Follow-up after explantation of a ventricular assist device

Table 4 :
Causes of death after ventricular assist device explantation due to myocardial recovery vulnerability of the body linked to the underlying original cardiac diagnosis.Furthermore, at least 5 children had to undergo ECMO support, a VAD reimplant or a heart transplant (HTx). or